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Here is a mind-boggling statistic. For everyminute you spend reading this article, onenew article will enter the world’s biomed-ical literature. Last year, 500,000 new arti-cles were published in more than 4,000journals archived by the National Libraryof Medicine’s MEDLINE Database. Even ifonly 1/1,000 of last year’s 500,000 articlescontain novel information that ultimatelyproves useful, we are still left with 500potentially important articles publishedeach year, any one of which could containthe first hint of a great scientific discovery.We are clearly immersed in a flood of infor-mation.

Given this relentless rise in scientificknowledge, how does a group of ordinarymortals, such as the 24 members of theLasker Jury, evaluate and rank the hundredsof different discoveries made over the lastseveral decades? I’ve wrestled with thisquestion for the past 10 years and couldnever come up with a satisfying answeruntil several months ago when I went to theRoof Garden at the Metropolitan Museumof Art in New York City.

Each summer, the Metropolitan Museuminvites a different artist to exhibit his or herwork at the Roof Garden that overlooksCentral Park. This year’s installation is bythe British sculptor Andy Goldsworthy.Goldsworthy is noteworthy and newswor-thy for his monumental environmentalsculptures made of stone and wood.

Inspired by the architectural backdrop ofCentral Park, Goldsworthy has created a 14-foot tower of 17 balanced stones—onestone stacked on top of another in a taperedpyramidal fashion (Fig. 1). As you lookfrom bottom to top, each successive stonebecomes smaller and smaller. The bottomstone is gigantic; it weighs 1.5 tons and is 5feet wide and 3 feet tall. The 17th stone at

the top is teeny; it weighs only 2 ounces andis the size of a silver dollar. The bottomstone is 20,000 times heavier than the topstone. To most viewers, this tapering towerof stones symbolizes a Manhattan sky-scraper. To me, the tower of Goldsworthyreveals how we decide which scientific dis-coveries are true milestones and prizewor-thy of being etched in Lasker stone.

There are two ways to viewGoldsworthy’s stone tower—from bottomto top or from top to bottom. Scientific dis-coveries can be viewed similarly. A typicalbottom-to-top discovery is the type thatyou read about every week in The New YorkTimes and USA Today: researcher X identi-fies a gene that will soon lead to a cure forcancer or schizophrenia. This bottom-uptype of discovery starts out like the bottomstone in Goldsworthy’s tower—with hugeimpact and tons of media coverage.However, other scientists soon find thatresearcher X’s bottom stone is not a step-ping-stone to new concepts, and with thepassage of time its impact diminishes likethe stones of Goldsworthy’s tower, viewedbottom to top.

The second type of discovery, the top-down type, is extraordinarily difficult tospot early on. That’s because it starts outlike the teeny stone at the top of theGoldsworthy tower—with little or noimpact and not an ounce of media cover-age. Other scientists soon find that thestone at the top is the stepping-stone thatunturns a new field of science. With thepassage of time, as ever more scientistsextend the initial discovery, its impactbecomes ever larger, like the stones ofGoldsworthy’s tower, viewed top to bot-tom. Because top-down discoveries ariseout of the blue, they are discoveries in thetrue sense of the word, and often many

years—sometimes decades—pass beforetheir full biological and medical impor-tance is appreciated.

Two of the most intensely studied mech-anisms of cell signaling, protein phospho-rylation and protein ubiquitination, areclassic examples of top-down discoveriesthat began in a modest way with virtuallyno impact and no media attention formany years. Thirty-four years passed fromthe time of phosphorylation’s discovery(1957) until the award of a Lasker Prize(1991), and 37 years until the award of theNobel Prize (1994). After ubiquitinationwas discovered in 1968, 22 years passedbefore the Lasker Prize was awarded(2000), and it is still waiting for Nobelrecognition. Like the awards for phospho-rylation and ubiquitination, the 2004Lasker Awards in Basic and ClinicalMedical Research celebrate toweringachievements that epitomize top-down sci-entific discoveries.

Basic Medical Research AwardThis year’s award in Basic Medical Researchis given to three scientists for discoveriesconcerning the superfamily of nuclear hor-mone receptors. Their research led to theelucidation of a unifying mechanism of cellsignaling that regulates diverse metabolicpathways that operate from embryonicdevelopment to adulthood. The three hon-ored scientists are Pierre Chambon (at theInstitute of Molecular and CellularGenetics and Biology in Strasbourg),Ronald Evans (at the Salk Institute in LaJolla, California) and Elwood Jensen (for-merly at the University of Chicago; now atthe University of Cincinnati College ofMedicine).

The story begins in 1956, when ElwoodJensen, an organic chemist at the time,

Towering science: an ounce of creativityis worth a ton of impactJoseph L Goldstein

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synthesized [3H]estradiol, injected imma-ture rats with it intravenously and noticedthat it accumulated only in tissues knownto grow in response to the hormone—the female reproductive tract. This now-historic experiment provided the first step-ping-stone to the discovery of the estrogenreceptor and subsequently to the receptorsfor all the other major steroid hormones,including testosterone and dihydrotestos-terone, progesterone, glucocorticoids,aldosterone and the steroidlike vitamin D.As is typical of top-down discoveries,Jensen’s first presentation in 1958 at a bio-chemistry congress in Vienna did not cre-ate much of a stir. It was attended by fivepeople, three of whom were other speakers.Jensen’s session coincided with a majorsymposium on steroid hormone action inwhich 1,000 people came to hear howestrogens act on target tissues by stimulat-ing the enzymatic production of NADPH,the prevailing concept at the time.

By 1980, after two decades of intensiveresearch, steroid hormone receptors came

to be viewed as ligand-dependent tran-scription factors that activate mRNA syn-thesis by binding to specific DNAsequences in their target genes. The attrac-tiveness of this receptor system for study-ing regulated gene transcription ineukaryotic cells caught the attention ofRonald Evans and Pierre Chambon. Theyrealized that, to explore steroid hormoneaction molecularly, they would need cDNAclones for the steroid hormone receptors.By early 1986, Evans had cloned andsequenced the cDNA for the glucocorticoidreceptor, and Chambon had done the samefor the estrogen receptor.

With their new molecular tools,Chambon and Evans, working independ-ently and uninterruptedly, made a series ofremarkable and unexpected observationsover the next 6 years. First, they discoveredthat the genes encoding the classic steroidhormone receptors belong to a superfamilyconsisting of 48 members that include thereceptors for thyroid hormone, retinoids(vitamin A and its derivatives), lipids (fatty

acids, prostaglandins, oxysterols, bileacids) and xenobiotics (drugs and foreignchemicals). Second, they developed a novelchimeric receptor strategy for identifyingligands for the so-called orphan nuclearreceptors. The first to be identified was all-trans-retinoic acid, the ligand for theretinoic acid receptor (RAR). The discov-ery of RAR was particularly noteworthy inthat it provided the molecular entrée toanalyzing vitamin A’s essential role inembryonic development and to solving thefirst three-dimensional structure of abound and unbound member of thenuclear receptor family.

Of the numerous Evans and Chambonexperiments, perhaps the most biologicallypregnant was the discovery of the retinoidX receptor (RXR). RXR is a promiscuousnuclear receptor family member that formsheterodimeric partnerships with 17 of its47 receptor siblings, including RAR, vita-min D receptor and thyroid hormonereceptor. These RXR liaisons are essentialfor each receptor’s specific DNA-bindingand gene-activating functions. The promis-cuous partnering property of RXR provedto be the Rosetta stone for discovering sev-eral hitherto-unknown nuclear receptors,many of which have profound implicationsfor normal physiology, disease pathogene-sis and drug discovery. Such receptorsinclude the peroxisome proliferator-activated receptor γ, which stimulates adi-pogenesis and is the target for the glitazoneclass of drugs that are used in the treatmentof type 2 diabetes; the liver X receptors andbile acid receptor, which regulate choles-terol homeostasis by activating genes forremoving cholesterol from the body; andthe pregnane X receptor, which activatesthe genes for P450 enzymes that detoxifydrugs and foreign chemicals that enter thebody.

In the past 45 years, many scientists havecontributed to the impressive body ofresearch that revealed the unimaginedsuperfamily of 48 nuclear receptors andtheir plethora of physiological actions. Yetthe discoveries of Jensen, Chambon andEvans stand out. Jensen, the patriarch ofthe field, established the paradigm with hispioneering work on the estrogen receptor,the matriarch of the superfamily. Evansand Chambon, with their superb molecularskills and creative biological insights,developed the grand sweep of the nuclearreceptor superfamily, revealing how itinfluences virtually every developmentaland metabolic pathway in animals andhumans.

Figure 1 British sculptor Andy Goldsworthy standing next to one of his stone towers during itsinstallation at the Iris and B. Gerald Cantor Roof Garden on top of The Metropolitan Museum of Art inNew York City. The exhibit, “Andy Goldsworthy on the Roof,” runs through October 31, 2004 (StoneHouses, 2004, wood and stone, courtesy of the artist and Galerie Lelong; Andy Goldsworthy;courtesy Galerie Lelong). Photograph by Karen L. Willis, The Metropolitan Museum of Art.

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Clinical Medical Research AwardThis award is given each year in celebrationof a scientific contribution that has pro-foundly improved the clinical care ofpatients. This year’s award is given to theperson who single-handedly revolution-ized the surgical removal of cataracts. Therecipient is the late Charles D. Kelman, whobefore his recent death in June 2004 was apracticing ophthalmologist affiliated withthe New York Eye and Ear Infirmary inNew York City.

Cataracts are the most common cause ofreversible blindness in the world, affectingabout 20 million people. More than one-half of the population over 65 years of agedeve-lops visual impairment caused bycataracts. Before Kelman’s pioneering work,cataract surgery was a major ordeal forpatients that required a hospital stay of 10days often accompanied by serious compli-cations, as well as a convalescence of severalmonths.

In 1967, Kelman developed a totally new way to remove cataracts that, over thenext 25 years, would replace traditionalinpatient cataract surgery with an outpa-tient procedure that is virtually free ofcomplications. Kelman called his proce-dure phacoemulsification (phako beingGreek for ‘lens’; emulsi for ‘milk out’). In itscurrently practiced form, phacoemulsifica-tion involves making a small incision in thecornea and then inserting an ultrasonicprobe, the sonic vibrations of which breakup and liquefy the cataractous lens. Theemulsified fragments of lens are then suc-tioned through the sonic tip, and a foldableintraocular lens is inserted through thesmall incision. Once inside the eye, theflexible lens unfolds like a parachute, andvisual acuity is restored typically to 20/20or 20/40. The entire procedure, which canbe done in 5–10 minutes, has now becomethe single most commonly performed elec-tive surgical operation in the westernworld. In the United States alone, nearlythree million Kelman-type cataract opera-tions were performed last year.

The idea for phacoemulsification cameto Kelman in 1964 in an epiphanousmoment while sitting in his dentist’s chairand having his teeth cleaned. This story isrecounted in my article on pages xix–xx,describing the story behind the develop-ment of phacoemulsification. As shown inFigure 2 of that article, from 1967 to 1985the impact of phacoemulsification, asjudged by the percentage of cataractsremoved by this procedure compared tothe traditional inpatient operation, was

tiny, like the top stone on the Goldsworthytower. With the passage of time, however,as Kelman and others improved the proce-dure, a steep rise in its acceptance tookplace; the percentage of all cataract opera-tions in the United States done by pha-coemulsification increased from 16% in1985 to 50% in 1990 and 97% in 1996. Thisis a towering achievement, illustratingagain how an ounce of creativity is worth aton of impact.

Special Achievement Award in MedicalSciencesThis award, inaugurated in 1994, is givenperiodically to honor a scientist whose life-time contributions to biomedical researchare universally admired and respected fortheir creativity, importance and impact.

This year’s award is given to Matthew S.Meselson of Harvard University. Meselsonis cited for a 50-year career in science thatcombines penetrating discovery in molecu-lar biology with creative leadership in pub-lic policy aimed at eliminating chemicaland biological weapons.

Meselson’s contributions to biochem-istry and genetics are legendary, beginningfrom his days as a graduate student in themid-1950s, when he invented the tech-nique of equilibrium density-gradient cen-trifugation for analyzing the density ofgiant molecules. He used this technique intwo classic experiments that were central tothe foundation on which molecular biol-ogy was built: first, the Meselson-Stahlexperiment in 1958, showing that DNAreplicates semiconservatively as predictedby the Watson-Crick model, and second,the Brenner, Jacob and Meselson experi-ment in 1961, demonstrating the existenceof mRNA. The history of the Meselson-Stahl experiment, often referred to as “themost beautiful experiment in biology,” isrecounted in a recent book by Frederic L.Holmes, entitled Meselson, Stahl, and theReplication of DNA (Yale University Press,2001).

In addition to DNA replication,Meselson has contributed in fundamentaland original ways to four other areas ofDNA biology: (i) DNA recombination(demonstration of breakage and cross-joining of two parental DNA moleculesand the concept of heteroduplex junctionbetween recombining molecules) (ii) DNArepair (the existence of methyl-directedmismatch repair for correcting mistakes inDNA) (iii) DNA restriction (the firstpurification of restriction enzymes andmethodology for their characterization),

and (iv) DNA evolution (molecular geneticanalysis of an aquatic invertebrate, Bdelloidrotifer, which defies current evolutionarythinking because it has evolved over tens ofmillions of years in the absence of sexualreproduction or genetic exchange).

Not content to be an armchair academicwho sits back and criticizes public policy,Meselson became a self-taught expert inbiological and chemical weapons and atireless campaigner for their abolition.Over the past 35 years, he has used his inci-sive thinking and scrupulous behavior toinfluence several major public policy deci-sions and events, including PresidentNixon’s 1969 decision to cancel the US gov-ernment’s offensive biological weaponsprogram;, the negotiation of the BiologicalWeapons Convention at Geneva in 1972and its ratification by the US Senate in1975;, the discovery that the puzzling phe-nomenon of ‘yellow rain’ in Southeast Asiaduring the 1980s was not a form of chemi-cal warfare dropped by communists but theharmless feces of honeybees; and, finally,the discovery that the epidemic inSverdlovsk, USSR that killed 60 people in1979 was caused by an airborne leak ofanthrax from a biological weapons facilityand not by tainted meat as originally pro-posed by the Russians.

‘Ingenious,’ ‘logical’ and ‘incisive’ arethree of the terms that Meselson’s scientificpeers repeatedly use to describe his bio-chemical and genetic experiments. Thesesame terms are apt descriptors of hisapproach to dealing with high governmentofficials and politicians in his efforts tocontrol the manufacture and spread ofchemical and biological weapons. Meselsonis a towering figure in science—a very spe-cial scholar who has contributed imagina-tively not only to discovery in chemistryand biology but also to prevention of itsmisuse.

Joseph L. GoldsteinChair, Lasker Awards Jury

Lasker Award recipients receive an hono-rarium, a citation highlighting their achieve-ments and an inscribed statuette of theWinged Victory of Samothrace, which is theLasker Foundation’s symbol of humankind’svictory over disability, disease and death.

To read the formal remarks of speakers atthe Lasker ceremony, as well as detailed information on this year’s awardees, pleaserefer to the Lasker website at: http://www.laskerfoundation.org/.

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